title: Synthesis and biological activity of hydroxy substituted phenyl-benzo[d]thiazole analogues for antityrosinase activity in B16 cells.
abstract: In this study, we synthesized hydroxy and/or alkoxy substituted phenyl-benzo[d]thiazole derivatives using substituted benzaldehydes and 2-aminothiophenol in MeOH. The structures of these compounds were established by (1)H and (13)CNMR and mass spectral analyzes. All synthesized compounds were evaluated for their mushroom tyrosinase inhibition activity. Out the 12 generated compounds, 2a and 2d exhibited much higher tyrosinase inhibition activity (45.36-73.07% and 49.94-94.17% at 0.01-20 μM, respectively) than kojic acid (9.29-50.80% at 1.25-20 μM), a positive control. The cytotoxicity of 2a and 2d was evaluated using B16 cells and the compounds were found to be nontoxic. Compounds 2a and 2d were also demonstrated to be potent mushroom tyrosinase inhibitors, displaying IC(50) values of 1.14±0.48 and 0.01±0.0002 μM, respectively, compared with kojic acid, which has an IC(50) value of 18.45±0.17 μM. We also predicted the tertiary structure of tyrosinase, simulated the docking with compounds 2a and 2d and confirmed that the compounds strongly interact with mushroom tyrosinase residues. Kinetic plots showed that 2a and 2d are competitive tyrosinase inhibitors. Substitutions with a hydroxy group at R(3) or both R(3) and R(1) of the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase. We further found that compounds 2a and 2d inhibit melanin production and tyrosinase activity in B16 cells. These results may assist in the development of new potent tyrosinase inhibitors against hyperpigmentation.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Kumjeong-Gu, Busan 609-735, Republic of Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Ha
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Park
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Park
authors.forename: Daeui
authors.initials: D
authors.lastname: Park
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Eun Kyeong
authors.initials: EK
authors.lastname: Lee
authors.forename: Yu Kyeong
authors.initials: YK
authors.lastname: Han
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kim
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000363:Agaricales / Q000201:enzymology; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D007700:Kinetics; D008543:Melanins / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011753:Pyrones / Q000633:toxicity
chemical_list: D052160:Benzothiazoles; D008543:Melanins; D011753:Pyrones; C011890:kojic acid; D014442:Monophenol Monooxygenase; C005465:benzothiazole